Cellular Id1 inhibits hepatitis B virus transcription by interacting with the novel covalently closed circular DNA-binding protein E2F4

作者全名："Wei, Jie; Shi, Yueyuan; Zou, Chunhong; Zhang, Hongpeng; Peng, Hui; Wang, Shilei; Xia, Lulu; Yang, Yuan; Zhang, Xiang; Liu, Junye; Zhou, Hua; Luo, Miao; Huang, Ailong; Wang, Deqiang"

作者地址："[Wei, Jie; Huang, Ailong; Wang, Deqiang] Chongqing Med Univ, Affiliated Hosp 2, Dept Infect Dis, Key Lab Mol Biol Infect Dis,Minist Educ,Inst Vira, Chongqing 400010, Peoples R China; [Shi, Yueyuan; Zou, Chunhong; Wang, Shilei; Xia, Lulu; Yang, Yuan; Zhang, Xiang; Liu, Junye; Wang, Deqiang] Chongqing Med Univ, Coll Lab Med, Chongqing 400016, Peoples R China; [Wei, Jie] Jinan Univ, Zhuhai Hosp, Zhuhai Peoples Hosp, Dept Clin Lab, Zhuhai 519000, Guangdong, Peoples R China; [Peng, Hui] Cedars Sinai Med Ctr, Div Gastroenterol, Davis Bldg,Room 3094,8700 Beverly Blvd, Los Angeles, CA 90048 USA; [Shi, Yueyuan; Luo, Miao] Peoples Hosp Yubei Dist Chongqing City, Dept Clin Lab, Chongqing 401120, Peoples R China; [Zhang, Hongpeng] Chongqing Hlth Ctr Women & Children, Dept Lab Med, Chongqing 401147, Peoples R China; [Zhou, Hua] Chongqing Med Univ, Affiliated Hosp 2, Dept Clin Lab, Chongqing 400010, Peoples R China"

通信作者："Wang, DQ (通讯作者)，Room 613,Coll Life Sci Bldg,1 YiXueYuan Rd, Chongqing 400016, Peoples R China.; Huang, AL (通讯作者)，Room 617,Coll Life Sci Bldg,1 YiXueYuan Rd, Chongqing 400016, Peoples R China."

来源：INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000741968300005

JCR分区：Q1

影响因子：9.2

年份：2022

卷号：18

期号：1

开始页：65

结束页：81

文献类型：Article

关键词：HBV; cccDNA; Id1; promoter

摘要："Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), which required developing novel therapies targeting the inhibition of HBV transcription and replication due to current limited treatment options. We explored novel target for the development of novel therapies targeting the inhibition of HBV replication and transcription. The expression of Id1 and E2F4 in HCC cells and tissues was detected by qRT-PCR and western blot. We investigated the Id1 and E2F4-mediated transcription of HBV infection by using HepG2.2.15, HepAD38, HepG2-NTCP cell lines and AAV/HBV-infected mice. Interactions between the two host proteins and viral covalently closed circular DNA (cccDNA) were assessed using subcellular localization, protein-protein interaction, chromatin immunoprecipitation, and luciferase assays. Ectopic Id1 significantly reduced HBV transcription and replication in both HBV-expressing cells and AAV/HBV-infected mice. Id1 and E2F4 could form a heterodimer to prevent E2F4 from promoting HBV transcription and replication. E2F4 could directly bind to cccDNA and activate the HBV core promoter in cell lines. Furthermore, in vitro binding experiments confirmed that the sequence 1758'-TTAAAGGTC-1766', which is highly conserved among HBV genotypes, is the target site of the E2F4 homodimer. The findings suggest that E2F4 function as novel cccDNA-binding protein to directly activate HBV transcription by binding to Cp promoter region. Our results highlight the ability that E2F4 represent a pan-potential therapeutic target against HBV transcription and provide more clues to better understand the life cycle of HBV."

基金机构："National Major Science and Technology Projects of China [2017ZX10202203, 2018ZX10732202]; National Natural Science Foundation of China [81661148057]; Natural Science Foundation of Chongqing [CSTC2018jscx-msybX0032, CSTC2016jcyjA0204]"

基金资助正文："We thank Haitao Guo (Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America) for valuable suggestions and Prof. Ninshao Xia for providing HepG2-NTCP cells and AAV/HBV-infected mice. We would like to thank Editage (www.editage.cn) for its linguistic assistance during the preparation of this manuscript. This work was supported by National Major Science and Technology Projects of China (grant numbers 2017ZX10202203, 2018ZX10732202); the National Natural Science Foundation of China (grant number 81661148057); and Natural Science Foundation of Chongqing (grant numbers CSTC2018jscx-msybX0032, CSTC2016jcyjA0204)."